Investigation of some benzoquinazoline and quinazoline derivatives as novel inhibitors of HCV-NS3/4A protease: biological, molecular docking and QSAR studies.

Morbidity and mortality due to hepatitis C virus (HCV) is a globe health concern. Hence, there is a persistent demand to design and optimize current HCV therapy and develop novel agents. HCV NS3/A4 protease plays an essential role in HCV life cycle and replication. Thus, HCV NS3/A4 protease inhibitors are one of the best therapeutic targets for the identification of novel candidate drugs. Recent studies have shown some benzoquinazolines as potent antiviral agents and promising HAV-3C protease inhibitors. In the present study, a series of benzo[]quinazolines (1-13) and their quinazoline analogues (14-17) were evaluated for their HCV-NS3/4A inhibitory activities using assay. Our results revealed that the target compounds inhibited the activity of the NS3/4A enzyme, (IC = 6.41 ± 0.12 to 78.80 ± 1.70 μM) in comparison to telaprevir (IC = 1.72 ± 0.03 μM) as a reference drug. Compounds 1, 2, 3, 9, 10 and 13 showed the highest activity (IC = 11.02 ± 0.25, 6.41 ± 0.12, 9.35 ± 0.19, 9.08 ± 0.20, 16.03 ± 0.34 and 7.21 ± 0.15 μM, respectively). Molecular docking was performed to study the binding modes of the docked-chosen benzo[]quinazolines, hydrogen bonding, and amino acid residues at the catalytic triad of the NS3/4A enzyme of HCV. The QSAR was determined to explore the relationships between the molecular structures of the targets and their biological activities by developing prediction models among the known HCV NS3/A4 inhibitors and then to predict the inhibitory activity of the target molecules synthesized.